Lipopolysaccharide treatment downregulates the expression of the pregnane X receptor, cyp3a11 and mdr1a genes in mouse placenta
Lipopolysaccharide treatment downregulates the expression of the pregnane X receptor, cyp3a11 and mdr1a genes in mouse placenta
复制标题
脂多糖处理下调小鼠胎盘中孕烷 X 受体、cyp3a11 和 mdr1a 基因的表达。
DOI：
10.1016/j.tox.2005.03.011
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发表时间：
2005-08-01
期刊：
影响因子：
4.5
通讯作者：
Xu, DX
中科院分区：
文献类型：
--
作者：
Chen, YH;Wang, JP;Xu, DX
细胞色素P4503A （CYP3A）是细胞色素P450单加氧酶超家族的成员。多药耐药1 （MDR1）基因属于atp结合盒（ABC）家族。妊娠X受体（Pregnane X receptor， PXR）是一种以配体依赖的方式调控靶基因转录的核受体。脂多糖（LPS）诱导的肝脏PXR、CYP3A和MDR1的下调已在一系列研究中得到证实。然而，LPS是否抑制胎盘中PXR、CYP3A和MDR1的表达尚不清楚。在本研究中，我们研究了LPS对小鼠胎盘中PXR、cyp3a11和mdr1a表达的影响。在妊娠第17天（gd）腹腔注射不同剂量的LPS （0.1 ~ 0.5 mg/kg）。采用RTPCR检测LPS处理后12时胎盘PXR、cyp3a11和mdr1a mRNA水平。结果显示，LPS显著下调PXR、cyp3a11和mdr1a mRNA水平，且呈剂量依赖性。用自由基自旋捕获剂α -苯基- n -t-丁基硝基酮（PBN）前后处理妊娠小鼠后，lps诱导的胎盘中PXR、cyp3a11和mdr1a mRNA下调明显减弱。进一步的实验表明，LPS增加了小鼠胎盘中脂质过氧化和促炎细胞因子的表达，而PBN也能减弱这些表达。此外，n -乙酰半胱氨酸（NAC）可阻止lps诱导的小鼠胎盘中PXR、cyp3a11和mdr1a mRNA的下调。NAC还能抑制lps引发的小鼠胎盘脂质过氧化、GSH耗竭和促炎细胞因子的表达。这些结果表明，LPS下调胎盘PXR、cyp3a11和mdr1a mRNA的表达。活性氧（ROS）可能参与了lps诱导的小鼠胎盘中PXR、cyp3a11和mdr1a的下调。(C) 2005年由爱思唯尔爱尔兰有限公司出版
The cytochrome P4503A (CYP3A) is a member of the cytochrome P450 monooxygenase superfamily. The multidrug resistance 1 (MDR1) gene belongs to the ATP-binding cassette (ABC) family. Pregnane X reccptor (PXR) is a nuclear receptor that regulates its target gene transcription in a ligand-dependent manner. Lipopolysaccharide, (LPS)-induced downregulation of PXR, CYP3A and MDR1 in liver has been demonstrated in a series of studies. However, it is not clear whether LPS represses the expression of PXR, CYP3A and MDR1 in placenta. In the present study, we investigated the effects of LPS on the expression of PXR, cyp3a11 and mdr1a in mouse placenta. Pregnant ICR mice were injected intraperitoneally with different doses of LPS (0.1-0.5 mg/kg) on gestational day (gd) 17. Placental PXR, cyp3a11 and mdr1a mRNA levels were determined at 12 It after LPS treatment using RTPCR. Results showed that LPS significantly downregulated PXR, cyp3a11 and mdr1a mRNA levels in a dose-dependent manner. LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in placenta was significantly attenuated after pregnant mice were pre- and post-treated with alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Additional experiments revealed that LPS increased lipid peroxidation and proinflammatory cytokine expressions in mouse placenta, all of which were also attenuated by PBN. Furthermore, LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in mouse placenta was prevented by N-acetylcysteine (NAC). NAC also inhibited LPS-initiated lipid peroxidation, GSH depletion and proinflammatory cytokine expressions in mouse placenta. These results indicated that LPS downregulates placental PXR, cyp3a11 and mdr1a mRNA expressions. Reactive oxygen species (ROS) may be involved in LPS-induced downregulation of PXR, cyp3a11 and mdr1a in mouse placenta. (C) 2005 Published by Elsevier Ireland Ltd.